ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.476A>T (p.Asp159Val)

gnomAD frequency: 0.00003  dbSNP: rs28931592
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000018551 SCV000800655 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2018-01-18 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000991848 SCV001143671 uncertain significance not provided 2019-06-12 criteria provided, single submitter clinical testing
Invitae RCV000991848 SCV002184991 uncertain significance not provided 2021-09-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 159 of the GJB2 protein (p.Asp159Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs28931592, ExAC 0.003%). This missense change has been observed in individual(s) with deafness (PMID: 12239718, 26061264; Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17024). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant disrupts the p.Asp159 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 14985372), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222355 SCV002500697 uncertain significance not specified 2022-03-28 criteria provided, single submitter clinical testing Variant summary: GJB2 c.476A>T (p.Asp159Val) results in a non-conservative amino acid change located in the cysteine-rich domain (IPR019570) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251102 control chromosomes (gnomAD). c.476A>T has been reported in the literature in at least two compound heterozygous individuals affected with Non-Syndromic Hearing Loss (Gualandi_2002, Kim_2015, Lee_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx RCV000991848 SCV002588394 uncertain significance not provided 2022-04-27 criteria provided, single submitter clinical testing Reported with a second variant (phase unknown) in unrelated patients with hearing loss in published literature (Gualandi et al., 2002; Kim et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26061264, 25388846, 12239718)
Fulgent Genetics, Fulgent Genetics RCV002504804 SCV002815785 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher 2022-03-17 criteria provided, single submitter clinical testing
OMIM RCV000018551 SCV000038833 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2002-09-15 no assertion criteria provided literature only
Natera, Inc. RCV000018551 SCV002086043 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2020-07-13 no assertion criteria provided clinical testing

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